MXPA01004649A - Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transplants. - Google Patents
Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transplants.Info
- Publication number
- MXPA01004649A MXPA01004649A MXPA01004649A MXPA01004649A MXPA01004649A MX PA01004649 A MXPA01004649 A MX PA01004649A MX PA01004649 A MXPA01004649 A MX PA01004649A MX PA01004649 A MXPA01004649 A MX PA01004649A MX PA01004649 A MXPA01004649 A MX PA01004649A
- Authority
- MX
- Mexico
- Prior art keywords
- cell
- antibody
- cells
- rituxan
- disease
- Prior art date
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
The use of a chimeric anti-CD20 antibody, RITUXAN(R), as an in vivo or in vitro purging agent, of patients receiving bone marrow or peripheral blood stem cell transplant during treatment of B-cell-related malignancies, e.g., B-cell lymphomas or leukemias, is disclosed. Such purging may enhance engraftment and/or prevent disease relapse in such patients.
Description
ANTI-CD20 CHEMOTERIC ANTIBODY TREATMENT FOR PATIENTS WHO RECEIVE BONE MARROW TRANSPLANTATIONS OR
PERIPHERAL BLOOD CELLS
FIELD OF THE INVENTION The use of an anti-CD20 antibody or fragment thereof as an in vi tro or in vi ve cleaning agent in patients receiving bone marrow transplantation or peripheral blood stem cell transplantation is described.
BACKGROUND OF THE INVENTION The use of antibodies to the CD20 antigen as diagnostic and / or therapeutic agents for B-cell lymphoma has previously been reported. CD20 is a useful marker or receptor for B-cell lymphomas, since this antigen is expressed at very high densities at the surface of malignant B cells, ie, B cells where non-knocked proliferation can lead to B cell lymphoma-s. CD20 or Bp35 is a differentiation antigen restricted by B lymphocyte that is expressed during the early development of pre-B cell, and remains until the differentiation of plasma cells. Some believe that the CD20 molecule could regulate a step in the process of B cell activation, which is required for the cycle of initiation and differentiation
Ref: 129320
j ^^ ¿, cell phone. Furthermore, as indicated, CD20 is usually expressed at very high levels of neoplastic ("tumor") B cells. The therapies reported earlier that involved anti-CD20 antibodies have involved the administration of a therapeutic anti-CD20 antibody, either alone or in conjunction with a second radiolabeled anti-CD20 antibody, or a chemotherapeutic agent. In fact, the Food and Drug Administration has approved the therapeutic use of such therapeutic anti-CD20 antibody, RITUXAN®, for use in relapsed and previously treated low-grade non-Hodgkin's lymphoma (NHL). Also, the use of RITUXAN® in combination with a radiolabeled murine anti-CD20 antibody for the treatment of B-cell lymphoma has been suggested.
However, while anti-CD20 antibodies, and in particular, RITUXAN®, have been reported to be effective for the treatment of B cell lymphomas, such as lymphoma_no Hodgkin, treated patients often undergo a relapse of the disease . Therefore, it would be beneficial if more effective antibody treatments could be developed. More specifically, it would be advantageous if other therapeutic applications of anti-CD20 antibodies were discovered. Also, it would be useful if the current treatment protocols for B-cell lymphoma were improved, which would prevent or further reduce the relapse of the disease.
BRIEF DESCRIPTION OF THE INVENTION Accordingly, it is an object of the invention to improve the problems of the above treatments for diseases related to B cells, eg, lymphomas and B-cell leukemias, in particular the problem of relapse of the disease after treatment of the disease. More specifically, it is an object of the invention to reduce the incidence of relapse of the disease in patients with diseases related to B cells receiving bone marrow or peripheral blood stem cell transplants, by the use of an anti-CD20 antibody. as a cleaning agent in vi tro and / or in vi ve before, concurrent and / or after transplant. It is an even more specific object of the invention to use RITUXAN® as a cleaning agent in vi tro and prior, concurrent and / or after transplantation of bone marrow or peripheral blood stem cells.
DETAILED DESCRIPTION OF THE INVENTION A significant problem associated with the treatment of diseases involving B cells and other cells expressing the CD20 antigen, which
T uife * - * iH * áta? d-i ^ i¿ include lymphomas and B cell leukemias, is the problem of relapse of the disease after treatment. The exact cause of the relapse of the disease is not clear. However, it is known that such a relapse could still occur in patients receiving aggressive therapeutic intervention, e.g., high dosages of chemotherapeutic agents, cytokines, radiation, and / or antibodies. While the exact cause of relapse
10 remains unclear, it is speculated by some researchers that the relapse of the disease could occur because the patient could still harbor low numbers of diseased cells, even after aggressive therapy. Also, it is speculated that the
Transplantation of bone marrow or transplanted tissue from peripheral blood stem cells could be contaminated on its own by diseased cells expressing the CD20 antigen, e.g., B-cell lymphoma cells. Therefore, transplantation of such tissues could
20 unknowingly introducing diseased cells, and thereby actually increasing the risk of a relapse of the disease. As discussed, the present invention seeks to prevent or reduce the incidence of the disease in
25 patients receiving a bone marrow or peripheral blood stem cell transplant, treating the bone marrow or transplanted peripheral blood stem cells
with an amount of anti-CD20 antibody or a fragment thereof, effective to clean the transplanted tissue from the cells expressing the CD20 antigen causing the disease. Such cleaning could be done in vi tro and / or in vi vo. For example, bone marrow or peripheral blood stem cells could be contacted with tissue culture with an anti-CD20 antibody before transplantation. In the preferred embodiment such antibody will comprise a chimeric, primate, primatized®, humanized, or human anti-CD20 antibody, preferably RITUXAN®. Alternatively, or in conjunction with such cleaning in vi tro, the patient could be treated concurrently or subsequent to transplantation of bone marrow or peripheral blood stem cells, with an amount of an effective anti-CD20 antibody to clean (in vi vo) or at least to reduce the number of cells expressing the CD20 antigen that causes the disease, which could occur in the transplant. Similarly, the antibody used for cleaning in vi will preferably comprise a chimeric, humanized, primate, primatized®, or human anti-CD20 antibody, preferably RITUXAN®. This cleanup could be carried out simultaneously or substantially contemporaneously with bone marrow or cell transplantation
The mother of peripheral blood, preferably, such cleaning will be carried out in a week or more, preferably from 1 to 12 hours after the transplant, however, such cleaning can be carried out up to approximately 1 to 100. days after transplantation In the preferred embodiment, in vivo cleaning will be performed in about 1 month after transplantation, more preferably in about one week after transplantation, and more preferably in about 1 to 12 hours after transplantation. stated earlier, the issue of cleanliness in vi ve or in vi tro of cells expressing the CD20 antigen will be desirably effected in patients who have been previously treated, in an effort to eradicate the B cells causing the disease, or other expressing cells. the CD20 antigen involved with the disease Such treatment methods include, by way of example, cytokine therapy, antibody therapies (eg, RITUXAN® or other antibodies directed to B cells), chemotherapy and / or radiotherapy, e.g., whole-body irradiation, radioimmunotherapy. In a particularly preferred embodiment, the subject of cleaning in vi ve or in vi tro will be carried out in patients who have been previously treated with RITUXAN® and / or radioimmunotherapy, who receive an autologous bone marrow or peripheral blood stem cell transplant after of RIT therapy and / or RITUXAN®. For example, patients who have a B cell-related disease, e.g., a lymphoma or B cell leukemia, will have their bone marrow or stem cells
5 peripheral blood collected before therapeutic treatment. This will be done by known methods. The patient will then undergo an aggressive therapeutic regimen, e.g., administration of RITUXAN®, or a radiolabeled antibody that is specific for an antigen expressed by the tumor cells, whole body irradiation, and / or a chemotherapy or cytokine. This therapeutic regimen will be carried out under conditions that are hypothetically designed to eradicate any B cells or other tumor cells that express the CD20 antigen, which may be present. After the treatment has been completed, the bone marrow or the peripheral blood stem cells, which could optionally be treated in vi tro with a
The anti-CD20 antibody, e.g., RITUXAN®, to deplete cells expressing CD20, is then transplanted into the patient to reconstitute the immune system thereof. Concurrently or soon after, the patient will be given an amount of an anti-CD20 antibody,
25 e.g., RITUXAN®, effective to cleanse any cell that causes the disease that may be present in bone marrow or stem cell transplantation.
^^^^^ gfijj peripheral blood. An effective dosage will typically comprise from about 0.01 to about 3.0 mg / kg of body weight. A preferred dosage will include from about 0.1 to about 20 mg / kg, more preferably from about 0.1 to about 5.0 mg / kg, administered in about one week of the transplant. The issue of cleaning in vi tro ylo in vi vo will reduce the risk of a relapse in many diseases related to B cells, eg, lymphomas or B-cell leukemias, such as non-Hodgkin's lymphoma, chronic lymphocytic leukemia, etc., after that treatment has been completed in patients receiving transplanted cells that could potentially be contaminated with cells that cause the disease. Also, the subject method should be tolerated well based on the relative non-toxicity of anti-CD20 antibodies, such as RITUXAN®, and therefore should not adversely impact the graft of transplanted autologous cells. In fact, it could act to promote the graft of such a transplant. As indicated in the preferred embodiment, the cleaning agent will contain RITUXAN®. However, other anti-CD20 antibodies, e.g., other chimeric, primate, primatized®, humanized or human antibodies could be used. Also, antibody fragments, e.g., Fv 's, FAB, F (ab)', F (ab2) 1, and aggregates thereof could be used. In addition, antibodies or antibody fragments directed to other surface markers of B cells, e.g., CD19, could also be used. Methods for producing chimeric, primate, primatized®, humanized and human antibodies are well known in the art. See, e.g., U.S. Pat. 5,5,30,101, published by Queen et al, U.S. Patent 5,225,539, published inter et al, U.S. 4,816,397 and 4,816,567, published by Boss et al, and Cabilly et al, respectively, all of which are incorporated by reference in their entirety. The selection of human constant regions could be significant for the therapeutic efficacy of the subject anti-CD20 antibody. In the preferred embodiment, the subject anti-CD20 antibody will comprise constant regions of human, gamma 1, or gamma 3, and more preferably, human gamma 1 constant regions. The use of anti-CD20 gamma 1 antibodies as therapeutics is described in the US patent 5,500,362, published by Robinson et al. Methods for making antibodies to human are also known and include, by way of example, production in SCID mice, and in vi tro immunization. As indicated, a particularly preferred anti-CD20 chimeric antibody is RITUXAN®, which is a chimeric anti-human CD20 gamma 1 antibody. The complete amino acid sequence and the corresponding nucleic acid sequence for this antibody could be found in U.S. Pat. 5,736,137, which is incorporated by reference in its entirety. This antibody, which is produced in a proprietary CHO cell expression system, commercialized by IDEC Pharmaceuticals Corporation, is made by means of a CHO cell transfectoma that was deposited on November 4, 1992 under the stipulations of the Budapest Treaty in the American Type Culture Collection, located at 12301 Parklawn Drive, Rockville, MD 20852. It was determined that this cell line is viable and would be replaced if it becomes non-viable during the term of the deposit. This cell line became irrevocably available in the issuance of the 5,736,137 patent and is available without restriction in the ATCC. This cell line will also be available without restriction during the lifetime of any patent that could be issued based on this application. The anti-CD20 antibody of the subjectWhen used as a cleaning agent, it will be administered by several administration routes, typically parenteral. This is planned to include intravenous, intramuscular, subcutaneous, rectal, vaginal administration, and administration with intravenous infusion is preferred. The anti-CD20 antibody will be used for therapeutic use by standard methods, e.g., by addition of
Are there any pharmaceutically acceptable buffers, e.g., sterile saline, sterile buffer water, propylene glycol, and combinations thereof.
5 EXAMPLE A single-branch pivotal study of Rituximab® was infused at 375 mg / m2 four times weekly, conducted in 166 patients with low-grade or follicular NHL (International Work Formulation [IWF]
10 A-D types and REAL classification, small lymphocytic lymphoma, follicular center, follicular grades I, II, III) due to relapse or persistence. (McLaughl inP, Grillo Lopez A, Link B, Levy R, Czuczman M, Williams M, Heyman M, Bence-Bruckler I, White C, Cabanillas F, Jain V, Ho
15 A, Lister J, Wey K, Shen D, Dallaire B. Rituximab® chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half patients responded to a 4-dose treatment program. Journal of Clinical Oncology 1998; 16: 2825-2833). Patients with tumor masses
20 > 10 e or with > 5000- 1 infocitos /: L in the peripheral blood were excluded from this study. The average age was 58 years (105 men and 61 women) and the average number of previous treatments was three. The bone marrow complication occurred in 56% of the
25 149 patients evaluated. Forty-five percent
had = 2 extranodal sites and 41% had disease
1
voluminous (= 5 cm).
The complete response required regression of all lymph nodes to < 1 X 1 cm2 demonstrated twice at least 28 days apart for the resolution of all symptoms and signs of lymphoma in the neck, chest, abdomen and pelvic CT records, and normalization of the bone marrow, liver and spleen. The partial response required a 5 50% decrease in the sum of the products of the perpendicular measurements of lesions without any evidence of progressive disease for at least 28 days. Patients who did not achieve a CR or PR were considered non-responsive, even if a net decrease (> 50%) of measurable disease was observed. The time for progression was measured from the first infusion to progression. The total response rate (ORR) was 48% with a rate of 6% CR and 42% PR (McLaughlin P, Grillo-Lopez A, Link B, Levy R, Czuczman M, Williams M, Heyman M, Bence -Bruckler I, White C, Cabanillas F, Jain V, Ho A, Lister J, Wey K, Shen D, Dallaire B. Rituximab® chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half patients responded to a 4-dose treatment program, Journal of Clinical Oncology 1998; 16: 2825-2833). The average progression time (TTP) for the response was 13.2 months and the average response duration (RD) was 11.6 months. Twenty-two of
á¡a-ÉuÍüiáiüMü «| igiaiiH * ---- - '- - - • > • 80 (28%) responses remain in continuous referral in 20.9+ to 32.9+ months (McLaughlin P, Grillo-Lopez A, Maloney D, Link B, Levy R, Czuczman M, Cabanillas F, Dallaire B, White C. Efficacy controls in long-term follow-up of patients treated with rituximab for relapsed or refractory, low grade or follicular NHL Blood 1998; 92: 414a-415a). The administration of Rituximab® resulted in a rapid and sustained depletion of B cells. B cells in the circulation were depleted within the first three doses with sustained exhaustion of up to six to nine months post-treatment in 83% of patients. The average levels of B cells returned to normal at 12 months after treatment. Although the average counts of NK cells remained unchanged, a positive correlation was observed between the absolute scores of higher NK cells in the baseline and the response to Rituximab® (Janakiraman N, McLaughlin P, White C, Maloney D, Shen D , Grillo-López A. Rituximab: Correlatioß between effector cells and clinical activity in NHL, Bl ood 1998; 92 (10 Suppl
1): 337a). Several baseline prognostic factors were analyzed to determine their correlation to the response. Significantly, in 23 patients with relapse after ABMT or PBSC, ORR was 78% versus 43% in patients who did not undergo dose therapy before
^ - * * * * high (p <0.01) This suggests that the anti-CD20 treatment could be effectively used to clear cells expressing the CD20 antigen in vi, when administered after transplantation. Furthermore, because 5 patients receiving high-dose prior therapy accompanied by bone marrow or peripheral blood stem cell transplantation, they seem to benefit more from subsequent therapy with Rituximab® than patients without pre-transplant therapy, this suggests that a
The combined treatment protocol that includes bone marrow or peripheral blood stem cell transplantation provides a synergistic effect when compared to each of the treatments alone. Although the present invention has been described in some
In the form of illustration and example, for purposes of clarity and understanding, it will be apparent that certain changes and modifications could be practical within the scope of the appended claims. It should be noted that with regard to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
25
Claims (6)
-
- Having described the invention as above, the content of the following claims is claimed as property: 1. A method for reducing the risk of relapse of a B-cell related disease in a patient receiving a bone marrow or stem cell transplant. Peripheral blood, characterized in that it comprises treating the transplant in vi tro and the in vi ve with an amount of an anti-CD20 antibody effective to reduce (cleanse) the number of cells expressing the anti-CD20 antigen causing the disease therein . 2. The method of claim 1, characterized in that the disease is a B cell lymphoma or leukemia.
- 3. The method of claim 1, characterized in that the cleaning is effected in vi ve by administering RITUXAN® not after approximately one month after of the transplant.
- 4. The method of claim 1, characterized in that RITUXAN® is administered in a dosage range of about 0.1 to 20 mg / kg, approximately one week after transplantation.
- 5. The method of claim 4, characterized because the patient receiving the transplant has previously been treated under conditions designed to eradicate the B cells that cause the disease. The method of claim 4, characterized in that the patient has previously been subjected to a treatment protocol selected from the group consisting of whole-body irradiation, immunotherapy with RITUXAN®, chemotherapy, cytokine therapy, radioimmunotherapy, or a combination thereof. / ANTI-CD20 CHEMOTERIC ANTIBODY TREATMENT FOR PATIENTS WHO RECEIVE BONE MARROW TRANSPLANTATIONS OR PERIPHERAL BLOOD CELLS SUMMARY OF THE INVENTION The use of a chimeric anti-CD20 antibody, RITUXAN®, as an in vi ve or in vi tro cleaning agent, of patients receiving bone marrow transplantation or peripheral blood stem cells during the treatment of malignant diseases related to B cell, eg, lymphomas or B-cell leukemias. Such cleansing could increase the graft and / or prevent relapse in such patients. T i l i -w
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US10765798P | 1998-11-09 | 1998-11-09 | |
PCT/US1999/024012 WO2000027433A1 (en) | 1998-11-09 | 1999-11-09 | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transplants |
Publications (1)
Publication Number | Publication Date |
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MXPA01004649A true MXPA01004649A (en) | 2002-05-06 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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MXPA01004649A MXPA01004649A (en) | 1998-11-09 | 1999-11-09 | Chimeric anti-cd20 antibody treatment of patients receiving bmt or pbsc transplants. |
Country Status (21)
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US (5) | US20040213784A1 (en) |
EP (1) | EP1131096B1 (en) |
JP (1) | JP2002529429A (en) |
KR (1) | KR20010099788A (en) |
CN (1) | CN1330554A (en) |
AT (1) | ATE454166T1 (en) |
AU (1) | AU761516B2 (en) |
BR (1) | BR9915149A (en) |
CA (1) | CA2350064C (en) |
CY (1) | CY1110681T1 (en) |
DE (1) | DE69941903D1 (en) |
DK (1) | DK1131096T3 (en) |
ES (1) | ES2338287T3 (en) |
HK (1) | HK1041811A1 (en) |
MX (1) | MXPA01004649A (en) |
MY (1) | MY155913A (en) |
PT (1) | PT1131096E (en) |
TR (1) | TR200101302T2 (en) |
TW (1) | TWI253934B (en) |
WO (1) | WO2000027433A1 (en) |
ZA (1) | ZA200103716B (en) |
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- 1999-11-09 WO PCT/US1999/024012 patent/WO2000027433A1/en not_active Application Discontinuation
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EP1131096A4 (en) | 2002-03-20 |
CN1330554A (en) | 2002-01-09 |
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MY155913A (en) | 2015-12-15 |
US20090074760A1 (en) | 2009-03-19 |
ES2338287T3 (en) | 2010-05-05 |
WO2000027433A1 (en) | 2000-05-18 |
CA2350064C (en) | 2012-05-08 |
US20040213784A1 (en) | 2004-10-28 |
ATE454166T1 (en) | 2010-01-15 |
AU1597000A (en) | 2000-05-29 |
AU761516B2 (en) | 2003-06-05 |
JP2002529429A (en) | 2002-09-10 |
BR9915149A (en) | 2001-08-07 |
US20140363424A1 (en) | 2014-12-11 |
DK1131096T3 (en) | 2010-05-17 |
EP1131096B1 (en) | 2010-01-06 |
PT1131096E (en) | 2010-04-14 |
ZA200103716B (en) | 2002-08-08 |
DE69941903D1 (en) | 2010-02-25 |
TWI253934B (en) | 2006-05-01 |
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